Mycobacteriostatic compositions



United States Patent 3,330,768 MYCOBACTERIOSTATIC COMPOSITIONS John Emyr Evans and Joseph Patrick Brown, Llangollen,

Wales, assignors to Monsanto Chemicals Limited, London, England, a British company No Drawing. Filed June 29, 1964, Ser. No. 378,964 3 Claims. (Cl. 252-407) This application is a continuation-in-part of application Ser. No. 99,704, filed Mar. 3 1, 1961, and now abandoned.

This invention relates to new mycobacteriostatic compositions, that is to say to compositions which exert both bacteriostatic and fun-gistatic activity.

In recent years much ettort has been expended in trying to find compounds which have mycobacteriostatic activity useful in special circumstances, for instance a mycobacteriostatic activity that is retained in the presence of deactivating materials such as soaps. Very many substances which have strong bacteriostatic properties in the absence of soaps, for instance chlorinated phenols, lose much or all of their activity when they are incorporated into such materials, and the search for a mycobacteriostatic compound which does not sufier from this disadvantage has proved a matter for prolonged research.

It has now been found that 6-ethoxy-2,2,4-trimethyl- 1,2'dihydro quinoline and its salts are very effective mycobacteriostats, particularly when used in soaps.

Accordingly, the invention comprises a soap composition which contains 6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline or its salt as mycobacteriostat.

Salts of 6-ethoxy-2,2,4 trimethyl-1,2-dihydroquinoline which can be used in the compositions of the invention include the acid-addition salts formed by treating the base with an acid such as hydrochloric or sulphuric acid, or for instance an organic acid such as acetic acid. Also suitable are the quaternary ammonium salts, such as the quaternary chlorides obtained by treating the free base with an alkyl chloride.

By soaps we mean the potassium or sodium salts of saturated or unsaturated fatty acids having 10 to 18 carbon atoms, prepared by the reaction of animal and vegetable glyceride oils with sodium or potassium hydroxides or with sodium or potassium carbonates. The soap can be for instance common soap (that is to say a sodium soap as defined above), but other soaps derived from natural oils, for example a potassium soap can be used. The soap incorporating the mycobacteriostat can if desired be made up in tablet form.

The dihydroquinoline or its salt can be incorporated in soaps by merely mixing with the molten soap and allowing the mixture to solidify; if convenient the free dihydroquinoline can be added in admixture with an organic solvent, such as ethyl alcohol. From 0.05 to and preferably from 0.5 to 3% of the mycobacteriostat by weight of the soap is suitable, though the amount incorporated in practice will depend upon the level of activity desired.

The general mycobacteriostatic activity of 6-ethoxy- 2,2,4-trimethyl-1-1,Z-dihydroquinoline and its superiority over other hydrogenated quinolines is illustrated by the following experimental results.

The minimum concentrations of the hydrogenated quinoline necesary to inhibit the growth of strains of various species of bacteria were measured as follows. 0.4 cc. of a 1% solution containing 1 gram of the compound per 100 cc. was incorporated into 20 cc. of a warm Oxoid Nutrient Broth No. 2 agar in a test tube giving a concentration of 0.02% of the compound in the medium. The warm agar was immediately poured into a sterile petri dish and when hard it was streaked with cultures of the test bacteria. The inoculated plate was incubated for 24 hours at 37 C., after which time it was examined for the presence or absence of growth of the organism. If any of the bacteria failed to grow at this concentration (i.e. 0.02%) the test was repeated at a lower concentration of the test compound until a concentration was reached at which the organism under test was found to grow. The concentration used in the test immediately preceding this, that is the lowest concentration at which the bacterium could not grow, was recorded as the minimum inhibitory concentration of the test compound for the bacteria in question.

To test the fungistatic activity of the compound a similar test procedure was used except that the sterile medium was a malt/Czapek Dox agar, the medium was stab inoculated, and the incubation period was 3 days at 25 C.

The results are shown in the following table, and the superiority of 6-ethoXy-2,2,4-trimethyl-l1,Z-dihydroquinoline is readily apparent.

Minimum Inhibitory Concentration, Percent Compound S M B 2 2 4-trimethyl-1 :2-dihydroquinoline 0. 01 0. 01 0. 02 2:2:4:6-tetramethyl-l:Z-dihydroquinoline. 0. 005 0. 005 0. 02 6ethyl-2: 2: 4-trimethyl-1 2-dihydr0quin0line" 0. 005 0. 005 0. 02 fi-isopropyl :2 -trime thyl-l Z-(lihydroqurnoline 0. 005 0. 005 N 6-t-b utyl 2 2: 4-trimethyl-1 :2-dihydroqu1n0- Ii 0. 005 0. 005 N 1i N N N G-ethox -2: 4-trimeth l1:2-dih dro linen? "Y 0. 005 0. 005 0. 002 2: 2: 4-trimethyl-1 :2: 3: 4-tetrahydroquinoline 0. 02 0. 02 0. 01 2: 2: 4-trimethyldecahydroquinoline N N N Diphenylamine acetone reaction product. 0. 005 0. 005 0. 02 N itroso 2:2: t-tri.methyl l Z-dihvdroquinonoline ca, (4 molecules) v N N N Polymerised 2: 2: 4-trimethyl-l :2-d1hydroqu1- -2 2 2- 0 nine- Bacteria: SStaph1flocuccus aureus; M-Bacillus mycaides. Fungus: B-Botrytis cinema. N=Not active at 0.02%.

The invention is illustrated by the following example.

Example This example describes the production of a bacteriosta- I tic soap composition containing 6-ethoxy-2,2,4-trimethyl- 1,2-dihydroquinoline and also demonstrates the bacteriostatic activity of the composition.

6 ethoxy 2,2,4 trimethyl-l,Z-dihydroquinoliue was thoroughly mixed with molten common soap (consisting essentially of the sodium salts of a mixture of fatty acids containing 10 to 18 carbon atoms) in a proportion sufficient to give a composition containing 4% by weight of the bacteriostat, and liquid was allowed to solidify.

The composition was dissolved in distilled water to give a 10% solution and 1.0 cc. of this solution was incorporated into 20 cc. of Oxoid Nutrient Broth No. 2 agar in a test tube, giving a final concentration of 0.02% of the bacteriostat. The minimum inhibitory concentration of the soap composition was then determined in the way described above. It was found that the 6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline, although it was mixed with twenty-five times its weight of common soap, had a minimum inhibitory concentration against Staphylococcus 3 aureus of 0.01%, which represented a very good bacteriostatic activity.

What is claimed is:

1. An antiseptic detergent consisting essentially of salts of fatty acids having from about 10 to about 18 carbon atoms of the class consisting of sodium and potassium salts, and from 0.05 to 5.0 percent by weight of 6-ethoxy- 2,2,4-trimethyl-ll,Z-dihydroquinoline.

2. An antiseptic detergent consisting essentially of sodium salts of fatty acids having from about 10 to about 18 carbon atoms and from about 0.05 to about 5.0 percent by weight of 6ethoXy-2,2,4-trimethy1-1,Z-dihydroquinoline.

3. An antiseptic detergent consisting essentially of potassium salts of fatty acids having from 10 to 18 carbon atoms, and from about 0.05 to about 5.0 percent by Weight of 6-ethoXy-2,2,4-trimethyl-1,Z-dihydroquinoline.

4 References Cited UNITED STATES PATENTS OTHER REFERENCES Frear, A Catalogue of Insectides and Fungicides, vol. II, Chronica Botanica (10., Mass., (1948), page 46.

1962, page 1226.

LEON D. ROSDOL, Primary Examiner.

Condensed Chemical Dictionary, Rose, Reinhold, N.Y.,

15 ALBERT T. MEYERS, SAMUEL H. BLECH,

S. E. DARDEN, Assistant Examiner.

Examiners. 

1. AN ANTISEPTIC DETERGENT CONSISTING ESSENTIALLY OF SALTS OF FATTY ACIDS HAVING FROM ABOUT 10 TO ABOUT 18 CARBON ATOMS OF THE CLASS CONSISTING OF SODIUM AND POTASSIUM SALTS, AND FROM 0.05 TO 5.0 PERCENT BY WEIGHT OF 6-ETHOXY2,2,4-TRIMETHYL-1,2-DIHYDROQUINOLINE. 